Учебники / Genetics and Auditory Disorders Keats 2002

has occurred in the family. One of the important goals of the genetic evaluation and counseling of the parents of deaf children has always been to try to identify the isolated genetic cases by clinical, genetic and (now) molecular criteria. Cases that were known a priori to be sporadic would not in general require molecular testing.

The existence of assortative mating among the deaf provides an alternative strategy for obtaining a robust estimate of the maximum frequency of Cx26 hearing loss in the deaf population. From the distribution of deaf and hearing offspring in DxD matings, segregation analysis permits estimation of the proportion of these marriages that can only have deaf children (noncomplementary matings), the proportion that can only have hearing children (complementary matings), and the remaining proportion capable of producing both deaf and hearing children. The non-complementary matings reflect marriages between individuals who are homozygous for recessive alleles at the same locus, and can therefore only produce deaf offspring. The complementary matings include marriages between individuals with nongenetic deafness, nongenetic deafness and recessive deafness, or different types of recessive deafness. Finally, the segregating matings include offspring with dominant or pseudodominant phenotypes. In Table 4.2, some

TABLE 4.2. Statistics and Parameter Estimates from

Segregation Analysesa

a Taken from Rose (1975)

82 W.E. Nance and A. Pandya

of the parameter estimates that were observed by Rose (1975) in her segregation analysis of the Fay data are given. In that large, unselected, nationwide sample of 1,299 DxD matings, Rose estimated that only 4.2% were non-complementary. It seems reasonable to assume that these marriages were random with respect to the cause of deafness. If it is assumed that every case of non-complementation resulted from deaf parents who were both homozygous for mutations at the Cx26 locus, the maximum possible frequency of the Cx26 phenotype in the deaf population would simply be the square root of 0.042, or about 20.1%. Molecular testing in a small contemporary sample of 16 apparently non-complementary matings suggests that currently only 76% rather than 100% involve Cx26 mutations, and there is reason to believe that fewer were attributable to this cause in the past. Thus, 17.8% would appear to be a conservative estimate of the maximum probable frequency of the Cx26 phenotype in the deaf population during the 19th century.

Current estimates, using molecular testing, suggest that at least 36% of probands referred to clinics for evaluation of congenital sensorineural hearing loss have Cx26 deafness, as do nearly 50% of probands from multiplex sibships (Green et al. 1999). It seems likely that the longstanding tradition of intermarriages among the deaf in this country is the explanation for the apparent doubling of the frequency of Cx26 deafness during the past 100 to 200 years (Nance et al. 2000). It is reasonable to assume that in previous millennia the genetic fitness (i.e., relative fertility) of individuals with profound prelingual deafness must have been very low, perhaps approaching zero. Under those circumstances, virtually all new cases of deafness would have been born to hearing parents. During the last two centuries, the social, economic and educational circumstances of the deaf have begun to improve. As mentioned this trend has been accompanied by an increase in the fertility of the deaf, along with the onset of a substantial degree of assortative mating in many, but not all, populations.

It is widely recognized that, for continuously distributed genetic traits such as stature, the tendency for like to marry like has increased the variance or variability of the population beyond what it would be if marriages occurred at random with respect to stature (Fisher 1918). For a qualitative genetic trait such as deafness, the effect of assortative mating is to increase the frequency of the phenotype. In the limiting case, if deafness were determined by recessive genes at a single locus, and if all deaf individuals married one another, deafness would double in frequency in the first generation after the onset of assortative mating. The frequency would then continue to increase until the incidence of deaf homozygotes began to approach the gene frequency in the population. This is the potential consequence of continued intermarriage among the deaf, which was of concern to A.G. Bell (Bell 1883).

Because of the extreme degree of genetic heterogeneity known to be associated with deafness, it has always been assumed that any effect of assorta-

tive mating on the frequency of deafness would be statistically trivial. The discovery that one form of recessive deafness is so much more common than all others, raises the possibility that this assumption may not be correct. In each generation after the appearance of assortative mating, the deaf children of deaf parents entered the new deaf-by-deaf mating pool, along with a substantially constant frequency of deaf offspring with genetic deafness who were born to hearing parents. However, the relative frequency of genes for different forms of recessive deafness should not be the same in the two groups. Among the former, many of the deaf offspring are the products of noncomplementary matings. Since the frequency of non-complementary matings for each type of recessive deafness is proportional to the fourth power of the respective gene frequencies, there is a strong bias towards the transmission of the most common form(s) of recessive deafness to the deaf offspring from these matings. The net effect of this process is the preferential transmission of Cx26 deafness to the deaf-by-deaf mating pool of the succeeding generation. This in turn will progressively increase the frequency of Cx26 deafness, the proportion of non-complementary matings, and the overall incidence of genetic deafness. Nonrandom mating by itself can only alter the genotype frequencies and not the underlying gene frequencies. But, when it is accompanied by relaxed selection, it can greatly accelerate the changes in gene frequency that can accompany attainment of a new mutational equilibrium. The magnitude of these effects will depend on many factors, including the number of recessive forms of deafness and their relative frequency, the overall proportion of deafness that is genetic, and the relative frequency and fertility of marriages among the deaf.

For any genetic trait, it is to be expected that gene and genotype frequencies vary in different populations; but in the case of the genes that cause deafness, the mating structure of the population is another important potential source of variation. Available data suggest that the incidence of Cx26 deafness in India (Green, personal communication), Mongolia (Pandya, personal communication), China (Liu, personal communication) and Japan (Fuse et al. 1999) is substantially lower than in populations where there has been a long tradition of intermarriages among the deaf. In the past, marriages among the deaf were virtually unheard of in India. In Mongolia, not a single one of 380 probands studied at the School for the Deaf in Ulan Bator was the offspring of a DxD mating. In China, Liu observed only two DxD matings among 184 marriages of the deaf (Liu et al. 1994). On the other hand, if there are populations in which the total proportion of Cx26 deafness is 50%, for example, then 25% of all marriages among the deaf should have all deaf offspring because of non-complementation.

In the limiting case, if all deafness in a population is caused by a recessive mutation at a single locus, 100% of marriages among the deaf should be non-complementary. This finding appears to characterize the genetic epidemiology of DFNB3 in the Balinese population reported by Friedman et al. (1995).

for Cx26 deafness is becoming more widely available in the deaf community, it is useful to assess the range of the potential effects that positive or negative marital selection for Cx26 genotypes might have on the overall incidence of deafness. Using data on the overall frequency of deaf children who are born to deaf parents (Table 4.2) and data on the frequency of pseudodominance and Cx26 deafness, it can be estimated that the complete avoidance of at-risk Cx26 marriages among the deaf would lead to approximately a 2% reduction in the overall incidence of deafness. Conversely, complete genotypic assortment for Cx26 deafness would lead to approximately an 8% increase in the first generation. The long-term effect of continued complete genotypic assortment would be the progressive reduction of heterozygotes in the population until the frequency of homozygotes began to approach the gene frequency of about 1.5% (Green et al. 1999). In comparison with phenotypic assortative mating, genotypic mate selection would greatly accelerate the approach to this limit. Nevertheless, despite the extreme nature of the alternative assumptions, the immediate effects of genotypic mate selection are relatively modest.

5.4 Estimating the Frequency of Common Forms

of Deafness

Clearly, the frequency of a common form of hearing loss such as Cx26 deafness can differ among racial or ethnic groups. Since it is a genetic form of deafness, the incidence will also differ in probands from simplex and multiplex sibships; and because of the mating structure of the deaf population, the incidence will even differ in the deaf offspring of deaf and hearing couples. For these reasons, obtaining reliable estimates of gene and genotype frequencies will require a random sample that includes proportionate representation from all relevant subgroups of the deaf population, or at least knowledge of the distribution of these subgroups, so that overall estimates can be reconstructed from stratified samples.

5.5 Other Examples of Nonrandom Mating

Phenotypic assortative mating is not the only form of nonrandom mating that can alter the frequency of genotypes from those expected under HardyWeinberg equilibrium. Inbreeding increases the frequency of all rare recessive phenotypes above the values expected with random mating. Similarly, were it not for racial and ethnic homogamy, the frequency of sickle cell anemia and Tay-Sachs disease (at conception) in this country would be far lower than the current incidence. These two diseases are useful examples for those who might be alarmed by the increase in the incidence of Cx26 deafness that appears to have occurred in this country during the past century. Marriages among the deaf are an integral part of a culture that has greatly enriched the lives of both the deaf and hearing segments of society during the past two centuries. Unless we are prepared to advocate the

86 W.E. Nance and A. Pandya

prohibition of racial and ethnic homogamy, there would appear to be no rational justification for deploring the effect that assortative mating may have had on the incidence of genetic deafness.

6. Summary

Interest in the genetics of deafness has a long history that predates the rediscovery of Mendelism. Throughout most of the twentieth century, geneticists argued about whether the genetics of deafness could best be explained by dominant or recessive genes at one, two, three, or perhaps four loci. By the 1970s, the concept of etiologic heterogeneity was well established. However, it seemed inconceivable that it would ever be possible to isolate and purify sufficient quantities of specific proteins from the cochlea to actually identify the functions of the mutant genes for the various forms of syndromic deafness that were being recognized. This volume is a testament to the revolutionary impact that molecular genetics has had on this field since that time. A unique feature or the genetic epidemiology of deafness is the cultural variation that exists in the mating structure of the deaf population. Now that the prevalence of specific genes in a population can be measured, we are beginning to appreciate the profound effect that recent changes in the mating structure have had on the frequency and distribution of genes for deafness.

One of the major limitations of man as the object of genetic research is the inability to perform experimental matings. As molecular testing for specific forms of genetic deafness becomes available, the existence of assortative mating among the deaf will ultimately provide an unparelleled opportunity to search for interactions among non-allelic genes for deafness. Since the conservation of phenotypes across species is far less complete than the conservation of orthologous gene sequences, phenotypes that result from interactions among genes are likely to be even less completely conserved. Human model systems will therefore be essential to recognize these effects. It should already be possible to ask, for example, if heterozygosity for a connexin 26 mutation alters the expression of Waardenburg syndrome, Pendred’s syndrome, the branchio-oto-renal syndrome, or Jervell and Lange-Nielsen syndrome. The work of Morell et al. (1997) provides hints on possible interactions between the WS 2 (MITF) and ocular albinism (TYR) genes, and the observations of Balciuniene et al. (1998, 1999) suggest apparent interactions between genes at the DFNA2 and the alpha tectorin locus. Thus, specific digenic interactions may be an important cause for variation in expressivity. However, as more deaf people get cochlear implants, the opportunity to document the effects of gene interactions on phenotype is likely to begin to disappear.

The knowledge that some forms of genetic deafness such as connexin 26 and A1555G are much more common than all other types in some populations has also made it possible to contemplate radical “postgenomic” strate-

gies for identifying new genes for deafness. With the successful completion of the mapping of the human genome, assigning functions to the genes that have been mapped has emerged as a major goal of research in human genetics. It may no longer be necessary to engage in the laborious collection and genotyping of samples from large pedigrees, consanguineous families or even sib pairs. By implementing a sequential screening strategy, beginning with the forms of deafness that are most common and easiest to test for, it may prove feasible to simply screen large repositories of DNA samples from probands in multiplex sibships for mutations in plausible candidate genes and/or murine orthologs by direct sequencing or other techniques. In this way, it may ultimately be possible to determine the frequencies of genes for deafness in different racial and ethnic groups, as well as the distribution of mutations in these genes.

Lastly, progress will undoubtedly be made in specific therapies to treat or prevent hearing loss. Biotinidase deficiency and streptomycin ototoxicity are perhaps the only forms of genetic hearing loss for which preventive pharmacologic treatment is already available, by providing supplemental biotin in the first instance, and avoiding aminoglycosides in the second. Dramatic though the results of cochlear implants have been, this therapy may some day be supplanted by the use of genetically corrected autologous stem cells to replace defective hair cells, or regenerate other specific cellular components of the cochlea. If one or more of these therapeutic approaches are successful, the 20th century may well have been the last in which deafness was a familiar part of the human experience.

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